(1) Field of the Invention
This invention relates generally to the labeling and detecting of tissues using radionuclides and, more particularly, to the intraoperative mapping of hyperactive parathyroid tissues using a radiopharmaceutical and a hand-held detector and the application of such in a method for performing a parathyroidectomy.
(2) Description of the Related Art
Primary hyperparathyroidism results from a single parathyroid adenoma in 87-92 percent of all cases. Removal of this one gland produces a long-term cure. Nevertheless, most surgeons have performed a complete bilateral neck exploration in patients with primary hyperparathyroidism in order to examine and sometimes biopsy each gland in order to be certain that all hyperfunctional parathyroid tissues are found and resected, leaving behind only normal glands. This approach has been a consequence of the historical inability of preoperative testing to accurately distinguish those patients harboring a single diseased gland from the eight to thirteen percent of patients with multiple adenomas or four gland hyperplasia.
This began to change in the early 1990's following the discovery that .sup.99m Tc Sestamibi, which had been used in cardiac imaging, preferentially concentrates in the parathyroid and can be used to localize parathyroid adenomas preoperatively (Taillefer et al., J. Nucl Med 33:1801-1807, 1992; Wei et al., Surgery 12:1111-1117, 1992). In the ensuing years, numerous surgeons have employed preoperative .sup.99m Tc Sestamibi in gamma surface mapping to identify and locate parathyroid adenomas (Denham et al., J Am Coll Surg 186:293-304, 1998).
.sup.99m Tc Sestamibi, which is a .sup.99m Tc complex with 6 methoxy-isobutyl-isonitrile (see U.S. Pat. Nos. 4,885,100 and 5,008,418 assigned to E. I. duPont de Nemours and Company), is taken up by both hyperactive parathyroid tissue and adjacent thyroid tissue. Nevertheless, because of a more rapid rate of washout of this substance from the thyroid compared to the parathyroid, it has been possible to distinguish parathyroid from thyroid tissue by employing an early followed by a delayed surface mapping in the region of the parathyroid glands in single radionuclide, double-phase radioscintigraphy (Tailleferet al., supra; Wei et al., Am J. Surg. 170:488-491, 1995; O'Doherty et al., J. Nucl. Med. 33:313-318, 1992). These earlier approaches using dual-phase surface mapping perform an initial scan at about 15 to 20 minutes after intravenously injecting the .sup.99m Tc Sestamibi followed by a delayed surface scan performed at anywhere from 90 minutes to 4 hours after injection (Billy et al., Am Surgeon 61:882-888, 1995; Yves et al., World J. Surg. 20:835-840, 1996; Carter et al., Am. Surgeon 63: 317-321; Martin et al., Am. J. Surg. 172:633-636, 1996; Caixas, et al., Surgery 121:53-541, 1997; Light et al., Am. Surgeon 62:562-568, 1996; Malhotra et al., Am. J. Surg. 172:63-64, 1996; McHenry et al., J. Am. College Surgeons 183:25-30, 1996). Although the use of dual-phase surface mapping constituted an advancement that improved the success rate of parathyroidectomy, nevertheless, not all parathyroid adenomas could be detected with a surface scan, particularly in multiglandular disease, such that bilateral neck dissection was still considered necessary for all parathyroidectomies (Martin et al., Am J Surgery 172:633-636, 1996).
At the same time that pre-operative dual-phase surface scanning was advancing parathyroidectomy methods, new hand-held imaging probes were being developed which allowed surgeons to identify radiolabeled cancers intraoperatively (see for example, U.S. Pat. Nos. 4,595,014 and 5,070,878). These probes were used to intraoperatively identify neoplasms and sentinel lymph nodes which could then be surgically removed (see U.S. Pat. Nos. 4,782,840 and 5,732,704). The use of such hand-held imaging probes during the operative procedure proved to be more effective in identifying neoplasms than surface mapping in that the hand-held intraoperative probe was often able to locate neoplasms that were not detected by the surface mapping (for example, see U.S. Pat. No. 4,782,840).
Recently, intraoperative mapping with a gamma probe has been used to facilitate the performance of parathyroidectomies (Norman et al., Am. Assoc. Endocrine Surgeons, Eighteenth Annual Meeting, page 21, Apr. 6-8, 1997). This early approach performed the surgery 3.+-.0.1 hours after Tc.sup.99 Sestamibi surface mapping, which would be expected to be about 3 hours and 15 minutes after injection of the radiopharmaceutical. Nevertheless, this early reported method would not be effective in identifying parathyroid adenomas because this report did not consider any possible interfering effect of adjacent thyroid tissue, which could limit the effective time during which any meaningful intraoperative mapping could be performed. Furthermore, the prior experience with pre-operative surface scanning would have provided no insight as to whether there would even be any interfering effect of adjacent thyroid tissue during intraoperative mapping because surface scanning would detect much less radioactivity than that measured deep in the neck at the site of a parathyroid adenoma and thyroid gland. This is due to the inverse square rule whereby the radioactivity significantly declines at increasing distances from the source. Indeed, as noted above, preoperative surface mapping was known to be a poor predictor of the presence of neoplasms, which were often not identified by the surface mapping, but found using an intraoperative probe. (see U.S. Pat. No. 4,782,840). In addition, as also noted above, surface mapping was known to sometimes fail to identify adenomas, whereas, as discussed below, 100% of adenomas can be identified using the intraoperative method disclosed herein. Thus, one would not have been able to predict whether thyroid tissue would interfere with detecting adjacent parathyroid adenomas and, if so, whether there would be a time window for performing intraoperative mapping of parathyroid adenomas.
Although other methods for localizing parathyroid adenomas have been studied such as the use of double-isotope surface mapping techniques, ultrasonography and intraoperative measurement of hormonal levels, these approaches have also proved to be less than completely effective in identifying all parathyroid adenomas (see for example, Keith et al., Am J. Surg. 166:357-359, 1993; Martin et al., Am J. Surg. 172:633-636, 1996; Chapuis et al., World J. Surg. 20:835-840, 1996;). Thus, there remains a continuing need to develop more effective methods for identifying parathyroid adenomas.